Use of Chlorprothixene and the Risk of Diabetes and Major Adverse Cardiovascular Events: A Nation-wide Cohort Study

Background: Chlorprothixene is commonly used off-label in low doses for sedative-hypnotic purposes, although it might carry an increased risk of cardio-metabolic adverse events due to its pharmacological profile.

Objectives: To investigate the risk of diabetes and major adverse cardiovascular events (MACE) with use of low-dose chlorprothixene in comparison with use of low-dose quetiapine.

Methods: Nation-wide cohort study, including all new users of low-dose chlorprothixene and low-dose quetiapine (both drugs ≤50mg tablets) in Denmark 2000-2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke, death from cardiovascular causes). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression models in high-dimensional propensity-score matched cohorts using intention-to-treat (ITT) and as-treated (AT) approaches to follow-up. The attributable proportion of cases (APC) were calculated for the main outcomes. An additional nested case-control analysis calculated odds ratios (ORs) for the association between different cumulative doses of chlorprothixene and the outcomes.

Results: Low-dose chlorprothixene use was associated with increased risk of diabetes (ITT-HR 1.16; CI 1.08-1.25; APC 14%), compared to low-dose quetiapine use. This association strengthened when follow-up was restricted to time on treatment (AT-HR 1.34; CI 1.14-1.56; APC 25%) and showed a clear difference from low-dose quetiapine evident beyond 3 years of continuous treatment. Low-dose chlorprothixene use was also associated with increased risk of MACE (ITT-HR: 1.12; CI: 1.04-1.21; APC 11%), and stroke (ITT-HR: 1.21; CI: 1.06-1.37), and possibly with myocardial infarction (ITT-HR: 1.11; CI: 0.95-1.30), but not with death from cardiovascular causes (ITT-HR: 1.07; CI: 0.96-1.20). These associations were not seen in AT-analyses. Cumulative dose of chlorprothixene ≥6000mg was associated with increased risk of diabetes (OR 1.15-1.63; test for trend p< 0.001), whereas a cumulative dose of chlorprothixene ≥1500mg was associated with increased risk of MACE (OR 1.10-1.85; test for trend p< 0.001).

Conclusions: Low-dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared to low-dose quetiapine use.